Education Committee Highlights WGC-2021 | part 6.3

NTG: If it’s not the pressure, then what is it?

Blame it on your parents (and their genes)
In this talk, Dr. Janey Wiggs highlights the different risk factors between NTG and high-tension POAG, specifically some genes associated with NTG. The importance of these is that they may be targets for neuroprotection and may help understand ganglion cell susceptibility in glaucoma.

Certain loci associated with NTG have also been associated with age-related degenerative diseases such as Alzheimer´s, cancer, etc., all of them showing dysregulation of cell senescence and division.
Genome regulatory sequences may also be implicated in the regulation of aqueous formation in NTG. Other findings suggest that ganglion cell susceptibility in NTG could also be mediated by dysregulation of genes coding for a transmembrane protein.

Dr Wiggs explains that in familiar forms of early-onset NTG, mendelian-inherited genes appear to be altered, such OPTN gene and TBK1, also implicated in neurogenerative diseases as Amyotrophic Lateral Sclerosis (ALS). She concludes that further studies are needed in order to understand the pathophysiology of NTG.

It’s about the ocular blood flow
In this talk Dr. Yukuhiro Shiga suggests that vascular abnormalities and IOP may contribute to NTG progression, findings also supported by the CNTGS. New image techniques allow to measure retinal vessel diameter, capillary perfusion density and ONH blood flow and they were found to correlate negatively with glaucomatous damage. Vascular autoregulation dysfunction plays a major role in glaucomatous damage as reduced capillary diameter and capillary blockage were associated with ganglion cell poor survival, and occurred before cell loss.

Pericytes and calcium homeostasis are probably involved in neurovascular degeneration although the specific underlying mechanisms remain unknown. He concludes that ocular blood flow assessment may help establish the patient´s risk of deterioration, and that pericytes should be considered as future therapeutic targets.

It’s your support system (the lamina cribrosa)
Dr. Crawford Downs explains that there is a translaminar pressure gradient given by the IOP on one side and the cerebrospinal fluid (CSF) counteracting on the other side of the lamina cribosa (LC), that affects cells regionally. Altered blood flow also plays an important role in the disease pathogenesis. LC defects, that are associated with visual field defects and specifically with NTG, may be consequence of active tissue remodeling occurring after IOP increase, as animal models suggest. Posterior laminar migration has also been observed.

Dr. Downs emphasizes that the LC is a dynamic structure that responses to the mechanical forces driven by IOP and CSF pressure around it. Remodeling can occur at all levels of IOP and CSF pressure, not particularly at high levels and is eye-specific. These findings support the asymmetry observed in some patients and the benefit of lowering IOP in NTG.

It’s the pressure from the other side (CSF pressure)
In this presentation, Dr. Ningli Wang presents evidence supporting the role of low CSF pressure and translaminar cribosa pressure in NTG. Some results may not be consistent because of small sample sizes and differences in procedures. Despite this, several studies have found as high as 70% of NTG patients to have reduced CSF pressure.

This was supported by animal studies and by longitudinal studies conducted in normal-tension hydrocephalus treated patients. It was also found that NTG patients with stable asymmetric visual loss tend to have LC defects and lower IOP in the eye with the affected VF. These results may trigger new therapeutic approaches such as posterior drainage to balance translaminar pressure gradient affecting the ONH.

Dr. Wang states the direction that studies should take: multicenter trials with standardized protocols and non-invasive CSF pressure measurements that may lead to new clinical applications of these findings.

It is the pressure!
Dr. Debbie Kamal states the importance of IOP in NTG, as in other types of glaucoma, and emphasizes that IOP remains the only modifiable factor to control the disease, even though genetic factors and individual susceptibility are also involved. Lowering IOP may be quite challenging in NTG since it remains by definition within the normal range but requires at least a 25% reduction to prevent progression, which may be achieved by surgery in the majority of patients. This was demonstrated in a study conducted by Dr. Kamal, in which after 10 years of follow up, although a few patients needed further surgeries, more than 80% of patients retain stability of VF, with a median time of progression of almost 90 months.

She looks forward non-invasive strategies such as neuroprotection to stop progressive NTG but remarks the importance of lowering IOP, usually by surgical means.

Watch the presentations